Combinations of isoform-targeted histone deacetylase inhibitors and bryostatin analogues display remarkable potency to activate latent HIV without global T-cell activation

AbstractCurrent antiretroviral therapy (ART) for HIV/AIDS slows disease progression by reducing viral loads and increasing CD4 counts. Yet ART is not curative due to the persistence of CD4+ T-cell proviral reservoirs that chronically resupply active virus. Elimination of these reservoirs through the administration of synergistic combinations of latency reversing agents (LRAs), such as histone deacetylase (HDAC) inhibitors and protein kinase C (PKC) modulators, provides a promising strategy to reduce if not eradicate the viral reservoir. Here, we demonstrate that largazole and its analogues are isoform-targeted histone deacetylase inhibitors and potent LRAs. Significantly, these isoform-targeted HDAC inhibitors synergize with PKC modulators, namely bryostatin-1 analogues (bryologs). Implementation of this unprecedented LRA combination induces HIV-1 reactivation to unparalleled levels and avoids global T-cell activation within resting CD4+ T-cells.</jats:p

Differential cross section for neutron-proton bremsstrahlung

The neutron-proton bremsstrahlung process $(np \to np\gamma)$ is known to be sensitive to meson exchange currents in the nucleon-nucleon interaction. The triply differential cross section for this reaction has been measured for the first time at the Los Alamos Neutron Science Center, using an intense, pulsed beam of up to 700 MeV neutrons to bombard a liquid hydrogen target. Scattered neutrons were observed at six angles between 12$^\circ$ and 32$^\circ$, and the recoil protons were observed in coincidence at 12$^\circ$, 20$^\circ$, and 28$^\circ$ on the opposite side of the beam. Measurement of the neutron and proton energies at known angles allows full kinematic reconstruction of each event. The data are compared with predictions of two theoretical calculations, based on relativistic soft-photon and non-relativistic potential models.Comment: 5 pages, 3 figure

Quality of Life in Menopausal Women: A Brazilian Portuguese Version of the Cervantes Scale

We present the translation, cultural adaptation and validation of the Cervantes Scale to Brazilian Portuguese. The Cervantes Scale (CS) was originally described in Spanish, and is a tool to measure health-related quality of life in perimenopausal and menopausal women. A cross-sectional study was carried out with 180 women aged 45 to 64 years. In addition to the CS, the following questionnaires were applied: Women's Health Questionnaire (WHQ) and abbreviated version of the World Health Organization's Quality of Life Questionnaire (Abbreviated WHOQOL-bref). In conclusion, the Brazilian Portuguese version of the CS is easy to apply and understand. The evaluation of its psychometric properties was satisfactory, and it can be applied to assess health-related QoL in Brazilian perimenopausal and menopausal women

O Brasil pós-1822:: nem tão moderno, nem tão conservador

This article deals with the accommodation of ideas in nineteenth - century Brazil, more specifically of the liberals in the economy and how they reverberated in the political environment of the country. There was a gap between theory and practice, for action departed from the idea of ​​the ruling class as an example and focus of the article, the slavery that was criticized by the European liberal discourse, but found resistance among the Brazilian liberals. Thus, liberal ideas, such as free trade, the right to property and individualism, were defended in the economy, however, were rejected when referring to slavery, which persisted in Brazil. To demonstrate this discrepancy between practice x theory, we use Alfredo Bosi, Roberto Schwarz and Carlos Lessa.Este artículo trata sobre la acomodación de ideas en el Brasil del siglo XIX, más específicamente de los liberales en la economía y cómo repercutieron en el entorno político del país. Hubo una brecha entre la teoría y la práctica, ya que la acción se apartó de la idea de la clase dominante como ejemplo y enfoque del artículo, la esclavitud que fue criticada por el discurso liberal europeo, pero que encontró resistencia entre los liberales brasileños. Así, las ideas liberales, como el libre comercio, el derecho a la propiedad y el individualismo, fueron defendidas en la economía, sin embargo, fueron rechazadas cuando se referían a la esclavitud, que persistía en Brasil. Para demostrar esta discrepancia entre la práctica y la teoría, usamos a Alfredo Bosi, Roberto Schwarz y Carlos Lessa.O presente artigo trata da acomodação de ideias no Brasil do século XIX, mais especificamente das liberais na economia e como reverberaram no meio político do país. Havia uma distância entre a teoria e a prática, pois a ação se afastava da ideia da classe dominante, como exemplo, e foco do artigo, a escravidão que era criticada pelo discurso liberal europeu, mas encontrava resistência entre os liberais brasileiros. Assim sendo, ideias liberais, como livre comércio, direito à propriedade e individualismo, eram defendidas na economia, no entanto, eram rechaçadas quando se referiam à escravidão, que perdurava no Brasil. Para demonstrar essa discrepância entre prática x teoria, utilizam-se Alfredo Bosi, Roberto Schwarz e Carlos Lessa

Characterization of designed, synthetically accessible bryostatin analog HIV latency reversing agents.

HIV latency in resting CD4+ T cell represents a key barrier preventing cure of the infection with antiretroviral drugs alone. Latency reversing agents (LRAs) can activate HIV expression in latently infected cells, potentially leading to their elimination through virus-mediated cytopathic effects, host immune responses, and/or therapeutic strategies targeting cells actively expressing virus. We have recently described several structurally simplified analogs of the PKC modulator LRA bryostatin (termed bryologs) designed to improve synthetic accessibility, tolerability in vivo, and efficacy in inducing HIV latency reversal. Here we report the comparative performance of lead bryologs, including their effects in reducing cell surface expression of HIV entry receptors, inducing proinflammatory cytokines, inhibiting short-term HIV replication, and synergizing with histone deacetylase inhibitors to reverse HIV latency. These data provide unique insights into structure-function relationships between A- and B-ring bryolog modifications and activities in primary cells, and suggest that bryologs represent promising leads for preclinical advancement

Delaware Physicians\u27 Behavior Regarding Patient Advice on Tobacco Use

No abstract available